Only three medications are approved by the Food and Drug Administration (FDA) for the treatment of alcohol dependence, namely disulfiram, naltrexone and acamprosate. However, the findings for efficacy of disulfiram are minimal and treatment effects for naltrexone and acamprosate are modest. There exists a substantial need for discovering ways to provide more effective treatments. Accordingly, identifying new potential neuropharmacological targets in the treatment of alcohol dependence represents a high priority of National Institute on Alcohol Abuse and Alcoholism (NIAAA). Ghrelin is a 28-amino acid peptide acting as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Ghrelin was first isolated from the stomach, but a central hypothalamic production of ghrelin has also been demonstrated. Ghrelin plays a key role in the regulation of appetite. Consistent with the common neurobiological substrates for control of food and alcohol consumption, preclinical investigations suggest that ghrelin plays a role in the neurobiology of alcohol dependence, thus representing a new potential neuropharmacology target. In keeping with the preclinical studies, our and other groups'human investigations showed how alcohol consumption affects blood ghrelin levels and that blood ghrelin levels significantly and positively correlate with craving measurements in alcohol-dependent individuals. The effects of exogenous ghrelin injected i.v. in alcohol-dependent individuals, however, have never been investigated. The current project proposes a randomized double-blind placebo-controlled 3-group between- subject laboratory study aimed at investigating the effects of exogenous ghrelin i.v. on non-treatment seeking alcohol-dependent subjects in terms of urges to drink, attention to cues and related psychophysiological measures. This Exploratory/Developmental project has the goals to: i) conduct an alcohol laboratory study testing the role of ghrelin i.v., therefore demonstrating the feasibility of such a study and the safety of ghrelin i.v. when administered to alcohol-dependent individuals;and ii) explore the effects of ghrelin i.v. on alcohol craving assessed under controlled conditions, such as a cue-reactivity experiment. This study will address whether alcohol craving is affected when ghrelin levels are modified acutely via a ghrelin i.v. injection. Given the crucial need to expand our understanding of the underlying neurobiology of alcoholism, this study potentially will lead to identify new targets for the development of pharmacological treatments that may improve interventions for alcohol dependent individuals. PUBLIC HEALTH RELEVANCE: Public Health Relevance Alcohol use disorders account for 100,000 excess deaths per year and considerable mortality and morbidity. There exists a substantial need for discovering new, more effective treatments for alcohol use disorders. Research has identified the ghrelin system as a mediator of alcohol craving. Better characterizing the role of ghrelin in the biobehavioral effects of alcohol may lead to more effective pharmacological treatments for alcohol use disorders.